Riley B. King was born on September 16, 1925, on a cotton plantation called Berclair, near the town of Itta Bena, Mississippi, the son of sharecroppers Albert and Nora Ella King. He considered the nearby city of Indianola, Mississippi to be his home. When Riley was four years old, his mother left his father for another man, so he was raised by his maternal grandmother, Elnora Farr, in Kilmichael, Mississippi.

In November 1941 "King Biscuit Time" first aired, broadcasting on KFFA in Helena, Arkansas. It was a radio show featuring the Mississippi Delta blues. King listened to it while on break at a plantation. A self-taught Guitarist, he then wanted to become a radio musician.

In 1943, King left Kilmichael to work as a tractor driver and play guitar with the Famous St. John's Quartet of Inverness, Mississippi, performing at area churches and on WGRM in Greenwood, Mississippi.

King was married twice, to Martha Lee Denton, November 1946 to 1952, and to Sue Carol Hall, 1958 to 1966. The failure of both marriages has been attributed to the heavy demands made by King's 250 performances a year. It is reported that he fathered 15 children with several different women. After his death, three more have come forward, claiming King as their father as well. Though neither of his marriages produced children, and biographer Charles Sawyer wrote that doctors found his sperm count too low to conceive children, King never disputed paternity of any of the 15 who claimed it, and by all accounts was generous in bankrolling college tuitions and establishing trust funds. In May 2016, the 11 surviving children initiated legal proceedings against King's appointed trustee over his estimated $30 million to $40 million estate. Several of them also went public with the allegation that King's Business manager, LaVerne Toney, and his personal assistant, Myron Johnson, had fatally poisoned him. Autopsy results showed no evidence of poisoning. A defamation suit filed by Johnson against the accusing family members (including his own sister, Karen Williams) is pending. Other children have filed lawsuits targeting King's music estate, which remains in dispute.

In 1949, King began recording songs under contract with Los Angeles-based RPM Records. Many of King's early recordings were produced by Sam Phillips, who later founded Sun Records. Before his RPM contract, King had debuted on Bullet Records by issuing the single "Miss Martha King" (1949), which did not chart well. "My very first recordings [in 1949] were for a company out of Nashville called Bullet, the Bullet Record Transcription company," King recalled. "I had horns that very first session. I had Phineas Newborn on piano; his father played drums, and his brother, Calvin, played guitar with me. I had Tuff Green on bass, Ben Branch on tenor sax, his brother, Thomas Branch, on trumpet, and a lady trombone player. The Newborn family were the house band at the famous Plantation Inn in West Memphis."

Following his first Billboard Rhythm and Blues chart number one, "3 O'Clock Blues" (February 1952), B.B. King became one of the most important names in R&B music in the 1950s, amassing an impressive list of hits including "You Know I Love You", "Woke Up This Morning", "Please Love Me", "When My Heart Beats like a Hammer", "Whole Lotta Love", "You Upset Me Baby", "Every Day I Have the Blues", "Sneakin' Around", "Ten Long Years", "Bad Luck", "Sweet Little Angel", "On My Word of Honor", and "Please Accept My Love". This led to a significant increase in his weekly earnings, from about $85 to $2,500, with appearances at major venues such as the Howard Theater in Washington and the Apollo in New York, as well as touring the entire "Chitlin' circuit". 1956 became a record-breaking year, with 342 concerts booked and three recording sessions. That same year he founded his own record label, Blues Boys Kingdom, with headquarters at Beale Street in Memphis. There, among other projects, he produced artists such as Millard Lee and Levi Seabury. In 1962, King signed to ABC-Paramount Records, which was later absorbed into MCA Records, and which itself was later absorbed into Geffen Records. In November 1964, King recorded the Live at the Regal album at the Regal Theater. King later said that Regal Live "is considered by some the best recording I've ever had . . . that particular day in Chicago everything came together . . ."

King's favorite singer was Frank Sinatra. In his autobiography he spoke about how he was a "Sinatra nut" and how he went to bed every night listening to Sinatra's classic album In the Wee Small Hours. During the 1960s Sinatra had arranged for King to play at the main clubs in Las Vegas. He credited Sinatra for opening doors to black entertainers who were not given the chance to play in "white-dominated" venues.

King was an FAA certified private pilot and learned to fly in 1963 at what was then Chicago Hammond Airport in Lansing, Illinois. He frequently flew to gigs but in 1995 his insurance company and manager asked him to fly only with another certified pilot. As a result, he stopped flying around the age of 70.

King gained further visibility among rock audiences as an opening act on the Rolling Stones' 1969 American Tour. He won a 1970 Grammy Award for the song "The Thrill Is Gone"; his version became a hit on both the pop and R&B charts. It also gained the number 183 spot in Rolling Stone magazine's 500 Greatest Songs of All Time.

In September 1970, King recorded Live in Cook County Jail, during a time in which issues of race and class in the prison system were prominent in politics. King also co-founded the Foundation for the Advancement of Inmate Rehabilitation and Recreation, tying in his support for prisoners and interest in prison reform. In addition to prison reform, King also wanted to utilize prison performances as a way to preserve music and songs in a similar way that Alan Lomax did.

B.B. King used simple equipment. He played guitars made by various manufacturers early in his career: he played a Fender Esquire on most of his recordings with RPM Records (USA). However, he was best known for playing variants of the Gibson ES-355. In 1980, Gibson Guitar Corporation launched the B.B. King Lucille model. In 2005, Gibson made a special run of 80 Gibson Lucilles, referred to as the "80th Birthday Lucille", the first prototype of which was given as a birthday gift to King, and which he used thereafter.

King was inducted into the Rock and Roll Hall of Fame in 1987, and is considered one of the most influential blues Musicians of all time, earning the nickname "The King of the Blues", and one of the "Three Kings of the Blues Guitar" along with Albert King and Freddie King. King was known for performing tirelessly throughout his musical career, appearing at more than 200 concerts per year on average into his 70s. In 1956 alone, he reportedly appeared at 342 shows.

King was diagnosed with type 2 diabetes in 1990. He lived with diabetes for over 20 years and was a high-profile spokesman in the fight against the disease, appearing in advertisements for diabetes-management products along with American Idol season nine contestant Crystal Bowersox.

In 1991, Beale Street developer John Elkington recruited B.B. King to Memphis to open the original B.B. King's Blues Club, and in 1994, a second club was launched at Universal Citywalk in Los Angeles. A third club in New York City's Times Square opened in June 2000. Two further clubs opened at Foxwoods Casino in Connecticut in January 2002 and another in Nashville in 2003. Another club opened in Orlando in 2007. A club in West Palm Beach opened in the fall of 2009 and an additional one, based in the Mirage Hotel, Las Vegas, opened in the winter of 2009.

In the 2000s to early 2010s, King was involved in the spread of awareness of diabetes since his diagnosis in 1990. He was also involved in a diabetes awareness campaign with American Idol contestant, Crystal Bowersox, with One Touch Ultra, starring in commercials and spreading awareness about diabetes and promoting diabetes health management.

In 2002, King signed on as an official supporter of Little Kids Rock, a nonprofit organization that provides free musical instruments and instruction to children in underprivileged public schools throughout the United States. He sat on the organization's Honorary Board of Directors.

In late October 2006, King recorded a concert album and video entitled B.B. King: Live at his B.B. King Blues Clubs in Nashville and Memphis. The four-night production featured his regular B.B. King Blues Band and captured his show as he performed it nightly around the world. Released in 2008, it was his first live performance recording in over a decade.

In 2007, King played at Eric Clapton's second Crossroads Guitar Festival and contributed the songs "Goin' Home", to Goin' Home: A Tribute to Fats Domino (with Ivan Neville's DumpstaPhunk) and "One Shoe Blues" to Sandra Boynton's children's album Blue Moo, accompanied by a pair of sock puppets in a music video for the song.

In the summer of 2008, King played at the Bonnaroo Music and Arts Festival in Manchester, Tennessee, where he was given a key to the city. Also in 2008, he was inducted into the Hollywood Bowl Hall of Fame.

King performed at the Mawazine festival in Rabat, Morocco, on May 27, 2010. In June 2010, King performed at the Crossroads Guitar Festival with Robert Cray, Jimmie Vaughan, and Eric Clapton. He also contributed to Cyndi Lauper's album Memphis Blues, which was released on June 22, 2010.

Rolling Stone ranked King at No. 6 on its 2011 list of the 100 greatest guitarists of all time.

B.B. King: The Life of Riley, a feature documentary about King narrated by Morgan Freeman and directed by Jon Brewer was released on October 15, 2012.

He used his signature model strings "Gibson SEG-BBS B.B. King Signature Electric Guitar Strings" with gauges: 10–13–17p–32w–45w–54w and D'Andrea 351 MD SHL CX (Medium 0.71mm, Tortoise Shell, Celluloid) Picks.

On October 3, 2014, after completing his live performance at the House of Blues in Chicago, a Doctor diagnosed King with dehydration and exhaustion, and the eight remaining shows of his ongoing tour had to be cancelled. King didn't schedule any additional shows for the remainder of the year.

On May 27, 2015, King's body was flown to Memphis. A funeral procession went down Beale Street, with a brass band marching in front of the hearse, playing "When the Saints Go Marching In". Thousands lined the streets to pay their last respects. His body was then driven down Route 61 to his hometown of Indianola, Mississippi. He was laid in repose at the B.B. King Museum and Delta Interpretive Center, in Indianola, for people to view his open casket. The funeral took place at the Bell Grove Missionary Baptist Church in Indianola, on May 30. He was buried at the B.B. King Museum.